Benzocycloalkylenylamine derivatives as muscarinic receptor antagonists

ABSTRACT

This invention relates to compounds which are generally muscarinic M2/M3 receptor antagonists and which are represented by Formula I:                    
     wherein X, Y, and Z are O, S, or NR 4 , and the other substituents are as defined in the specification; and prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use as therapeutic agents.

CROSS-REFERENCE TO RELATED INVENTIONS

This application is a divisional of Ser. No. 10/289,055 filed Nov. 6,2002 now U.S. Pat. No. 6,645,958 (under Title 35 U.S.C. 121, which is adivisional of Ser. No. 09/862,522 filed May 22, 2001, now U.S. Pat. No.6,500,822 which claims benefit under Title 35 U.S.C. 119(e) of U.S.Provisional Applications Nos. 60/207,483 filed May 25, 2000; and60/267,617 filed Feb. 9, 2001, all applications are hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

This invention relates to benzocycloalkylenylamine derivatives,associated pharmaceutically acceptable salts, or hydrates thereof, andassociated pharmaceutical compositions and methods for use as M2/M3selective muscarinic receptor antagonists.

BACKGROUND OF THE INVENTION

Acetylcholine (Ach) is the principal transmitter of the parasympatheticnervous system. The physiological actions of Ach are mediated byactivation of either nicotinic or muscarinic receptors. Both of thesereceptor classes are heterogeneous: e.g., the muscarinic receptor familycomprises five subtypes (M₁, M₂, M₃, M₄, and M₅) each encoded bydistinct genes and possessing unique pharmacology and distribution.

Almost all smooth muscle tissues express both muscarinic M2 and M3receptors, both of which have a functional role. M2 receptors outnumberM3 receptors by a proportion of approximately 4 to 1. Generally, M3receptors mediate the direct contractile effects of acetylcholine in thevast majority of smooth muscle tissues. M2 receptors, on the other hand,cause smooth muscle contraction indirectly by inhibiting sympathetically(β-adrenoreceptor)-mediated relaxation.

Compounds that act as antagonists of muscarinic receptors have been usedto treat several disease states associated with improper smooth musclefunction. Until recently, most of these compounds have beennon-selective for the various muscarinic receptor subtypes, leading tounpleasant anti-cholinergic side-effects such as dry mouth,constipation, blurred vision, or tachycardia. The most common of theseside-effects is dry-mouth resulting from muscarinic receptor blockade inthe salivary gland. Recently developed M2 or M3 specific antagonistshave been shown to have reduced side effects. Evidence suggests thatconcurrent blockade of M2 and M3 receptors could be therapeuticallyeffective in the treatment of disease states associated with smoothmuscle disorders.

Few M2/M3 selective antagonists have been developed. The presentinvention fills this need by providing these types of antagonists usefulin the treatment of disease states associated with improper smoothmuscle function.

SUMMARY OF THE INVENTION

This invention relates to compounds comprising Formula I:

wherein:

R¹, and R² are independently in each occurrence hydrogen, halogen,(C₁₋₆)-alkyl, —OR′, —SR′, —NR′R″, —SOR′, —SO₂R′, —COOR′, —OCOR′,—OCONR′R″, —OCONR′R″, —OSO₂R′, —OSO₂NR′R″; —NR′SO₂R″, —NR′COR″,—SO₂NR′R″, —SO₂(CH₂)₁₋₃CONR′R″, —CONR′R″, —NR′CONR′R″, cyano, haloalkyl,or nitro;

R′ and R″ are independently in each occurrence hydrogen, (C₁₋₆)-alkyl,haloalkyl, aryl, heterocyclyl, heteroaryl, aryl-(C₁₋₃)-alkyl,heteroaryl-(C₁₋₃)-alkyl, heterocyclyl-(C₁₋₃)-alkyl, cycloalkylalkyl,cycloalkyl, or R′ and R″ together with the nitrogen they are attachedmay also form a 5- to 7-membered ring, optionally incorporating oneadditional ring heteroatom chosen from N, O or S(O)₀₋₂;

R³ is independently in each occurrence (C₁₋₆) alkyl, (C₁₋₆) alkenyl,(C₁₋₆) alkynyl, or cycloalkyl;

one of X, Y or Z is independently S, O, or N—R⁴, the others are CH₂;

R⁴ is hydrogen, (C₁₋₆)-alkyl, haloalkyl, aryl(C₁₋₆)alkyl,heteroaryl(C₁₋₆)alkyl, —(C₁₋₆)—CR′R′R′, —COOR′, —SO₂R′, —C(O)R′,—SO₂(CH₂)₀₋₃NR′R″, —CONR′R″, or —PO(OR′)₂, where R′ and R″ are asdefined above;

m is an integer from 0 to 3 inclusive;

n is an integer from 1 to 6 inclusive;

p is an integer from 1 to 3 inclusive; and prodrugs, individual isomers,racemic or non-racemic mixtures of isomers, and pharmaceuticallyacceptable salts or solvates thereof.

In a preferred embodiment p is 2.

In another preferred embodiment p is 2, and one of X, Y or Z is NR⁴ andthe others are CH₂; in another embodiment p is 2, and one of X, Y or Zis NR⁴ and the others are CH₂, wherein R⁴ is hydrogen.

In another preferred embodiment, p is 2 and m is 1; in another preferredembodiment p is 2, m is 1 and Y is NR⁴ and the others are CH₂ and inanother preferred embodiment p is 2, m is 1 and one of X is NH and theothers are CH₂; In another preferred embodiment, p is 2, m is 2; inanother preferred embodiment, p is 2, m is 2, and one of X, Y or Z isNR⁴ and the others are CH₂, and in another preferred embodiment p is 2,m is 2, and one of X is NH and the others are CH₂.

In another embodiment n is 3 and p is 2, in another embodiment n is 3,and one of X, Y or Z is NR⁴ and the others are CH₂; in anotherembodiment n is 3, p is 2 and one of X, Y, or Z is NR⁴ and the othersare CH₂ in another embodiment n is 3, p is 2 and one of X, Y, or Z is NHand the others are CH₂. In another preferred embodiment n is 3, p is 2,m is 2 and one of X, Y, or Z is NR⁴ and the others are CH₂; and inanother preferred embodiment n is 3, p is 2, m is 2, X is NH, and Y andZ are CH₂. In another preferred embodiment n is 3, p is 2, m is 2, Y isNH and X and Z are CH₂. In another preferred embodiment n is 3, p is 2,m is 2, Z is NH and X and Y are CH₂.

In another embodiment n is 3 and one of X, Y, or Z is NR⁴ and the othersare CH₂.

In another preferred embodiment p is 2, m is 2, n is 3, one of X, Y or Zis O and the others are CH₂.

In a preferred embodiment, the invention further relates topharmaceutical compositions containing a therapeutically effectiveamount of at least one compound of Formula I, or prodrugs, individualisomers, racemic or non-racemic mixtures of isomers, or pharmaceuticallyacceptable salts or solvates thereof, in admixture with at least onesuitable carrier. In a more preferred embodiment, the pharmaceuticalcompositions are suitable for administration to a subject having adisease state which is alleviated by treatment with a muscarinic M2/M3receptor antagonist.

In another aspect, the invention relates to methods for treating asubject having a disease state that is alleviated by treatment with amuscarinic M2/M3 receptor antagonist, which comprises administering tosuch a subject a therapeutically effective amount of at least a compoundof Formula I. In a preferred embodiment, the subject has a disease statecomprising smooth muscle disorders; preferably genitourinary tractdisorders, respiratory tract disorders, gastrointestinal tractdisorders; more preferably genitourinary tract disorders such asoveractive bladder or detrusor hyperactivity and its symptoms, such asthe changes symptomatically manifested as urgency, frequency, reducedbladder capacity, incontinence episodes, and the like; the changesurodynamically manifested as changes in bladder capacity, micturitionthreshold, unstable bladder contractions, sphincteric spasticity, andthe like; and the symptoms usually manifested in detrusor hyperreflexia(neurogenic bladder), in conditions such as outlet obstruction, outletinsufficency, pelvic hypersensitivity, or in idiopathic conditions suchas detrusor instability, and the like. In another preferred embodiment,the disease comprises respiratory tract disorders such as allergies andasthma. In another preferred embodiment, the disease state comprisesgastrointestinal disorders.

In another aspect, the invention relates to a process for preparing acompound of Formula I, which process comprises reacting a compoundhaving a general formula

with a compound of general formula

to provide a compound of Formula I:

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise.

“Lower alkyl” means the monovalent linear or branched saturatedhydrocarbon radical, having from one to six carbon atoms inclusive,unless otherwise indicated. Examples of lower alkyl radicals include,but are not limited to, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl,sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.

“Substituted lower alkyl” means the lower alkyl as defined herein,including one to three substituents, preferably one substituent such ashydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro,thiol. These groups may be attached to any carbon atom of the loweralkyl moiety. Examples of substituted lower alkyl radicals include, butare not limited to, 2-methoxyethyl, 2-hydroxy-ethyl,dimethyl-aminocarbonylmethyl, 4-hydroxy-2,2-dimethyl-butyl,trifluoromethyl, trifluorobutyl and the like.

“Alkylene” means the divalent linear or branched saturated hydrocarbonradical, having from one to six carbons inclusive, unless otherwiseindicated. Examples of alkylene radicals include, but are not limitedto, methylene, ethylene, propylene, 2-methyl-propylene, butylene,2-ethylbutylene, and the like.

“Alkenyl” means the monovalent linear or branched unsaturatedhydrocarbon radical, containing a double bond and having from two to sixcarbon atoms inclusive, unless otherwise indicated. Examples of alkenylradicals include, but are not limited to, ethenyl, allyl, 1-propenyl,2-butenyl, and the like.

“Alkynyl” means the monovalent linear or branched unsaturatedhydrocarbon radical, containing a triple bond and having from two to sixcarbon atoms inclusive, unless otherwise indicated. Examples of alkynylradicals include, but are not limited to, ethynyl, 1-propynyl,2-butynyl, propargyl, and the like.

“Alkoxy” means the radical —O—R, wherein R is a lower alkyl radical asdefined herein. Examples of alkoxy radicals include, but are not limitedto, methoxy, ethoxy, isopropoxy, and the like.

“Aryl” means the monovalent aromatic carbocyclic radical consisting ofone individual ring, or one or more fused rings in which at least onering is aromatic in nature, which can optionally be substituted with oneor more, preferably one or two, substituents selected from hydroxy,cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unlessotherwise indicated. Alternatively two adjacent atoms of the aryl ringmay be substituted with a methylenedioxy or ethylenedioxy group.Examples of aryl radicals include, but are not limited to, phenyl,naphthyl, biphenyl, indanyl, anthraquinolyl, tert-butyl-phenyl,1,3-benzodioxolyl, and the like.

“Arylalkyl” means the radical R′R″-, wherein R′ is an aryl radical asdefined herein, and R″ is an alkyl radical as defined herein. Examplesof arylalkyl radicals include, but are not limited to, benzyl,phenylethyl, 3-phenylpropyl, and the like.

“Cycloalkyl” means the monovalent saturated carbocyclic radicalconsisting of one or more rings, preferably one or two rings, of threeto eight carbons per ring, which can optionally be substituted with oneor more, preferably one or two substitutents, selected from hydroxy,cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unlessotherwise indicated. Examples of cycloalkyl radicals include, but arenot limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl,cycloheptyl, and the like.

“Cycloalkylalkyl” means the radical R′R″-, wherein R′ is a cycloalkylradical as defined herein, and R″ is an alkyl radical as defined herein.Examples of cycloalkylalkyl radicals include, but are not limited to,cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, and the like.

“Heteroaryl” means the monovalent aromatic cyclic radical having one ormore rings, preferably one to three rings, of four to eight atoms perring, incorporating one or more heteroatoms, preferably one or two,within the ring (chosen from nitrogen, oxygen, or sulfur), which canoptionally be substituted with one or more, preferably one or twosubstituents selected from hydroxy, cyano, lower alkyl, lower alkoxy,lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro,alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl,alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated.Examples of heteroaryl radicals include, but are not limited to,imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl,quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl,benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzopyranyl, indazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl,naphthyridinyl, benezenesulfonyl-thiophenyl, and the like.

“Heteroarylalkyl” (or “heteroaralkyl”) means the radical of the formulaR′R″, wherein R′ is a heteroaryl radical as defined herein, and R″ is analkylene radical as defined herein. Examples of heteroarylalky radicalsinclude, but are not limited to, 2-imidazolylmethyl, 3-pyrrolylethyl,and the like.

“Heterocyclyl” means the monovalent saturated cyclic radical, consistingof one or more rings, preferably one to two rings, of three to eightatoms per ring, incorporating one or more ring heteroatoms (chosen fromN, O or S(O)₀₋₂), and which can optionally be substituted with one ormore, preferably one or two substituents selected from hydroxy, oxo,cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unlessotherwise indicated. Examples of heterocyclic radicals include, but arenot limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and the like.

“Heterocycloalkyl” (or “heterocyclylalkyl”) means the radical of theformula R′R″, wherein R′ is a heterocyclic radical as defined herein,and R″ is an alkylene radical as defined herein. Examples ofheterocycloalkyl radicals include, but are not limited to,1-piperazinylmethyl, 2-morpholinomethyl, and the like.

“Halogen” means the radical fluoro, bromo, chloro, and/or iodo.

“Haloalkyl” means the lower alkyl radical as defined herein substitutedin any position with one or more halogen atoms as defined herein.Examples of haloalkyl radicals include, but are not limited to,1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

“Hydroxyalkyl” means the lower alkyl radical as defined herein,substituted with one or more hydroxy groups. Examples of hydroxyalkylradicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and2-(hydroxymethyl)-3-hydroxypropyl, and the like.

“Acyloxy” means the radical —OC(O)R, wherein R is a lower alkyl radicalas defined herein. Examples of acyloxy radicals include, but are notlimited to, acetoxy, propionyloxy, and the like.

“Alkoxycarbonyl” or “alkyl ester” means the radical —C(O)—O—R, wherein Ris a lower alkyl radical as defined herein. Examples of alkoxycarbonylradicals include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, sec-butoxycarbonyl, isopropyloxycarbonyl, and the like.

“Aryloxycarbonyl” or “aryl ester” means the radical —C(O)—O—R, wherein Ris an aryl radical as defined herein. Examples of aryloxycarbonylradicals include, but are not limited to phenyl ester, naphthyl ester,and the like.

“Arylalkoxycarbonyl” or “arylalkyl ester” means the radical —C(O)—O—RR′,wherein R is a lower alkyl radical and R′ is an aryl radical as definedherein. Examples of aryloxycarbonyl radicals include, but are notlimited to benzyl ester, phenyl ethyl ester, and the like.

“Alkylcarbonyl” (or “acyl”) means the radical R—C(O)—, wherein R is alower alkyl radical as defined herein. Examples of alkylcarbonylradicals include, but are not limited to, acetyl, propionyl, n-butyryl,sec-butyryl, t-butyryl, iso-propionyl and the like.

“Arylcarbonyl” means the radical R—C(O)—, wherein R is an aryl radicalas defined herein. Examples of arylcarbonyl radicals include, but arenot limited to, benzoyl, naphthoyl, and the like.

“Arylalkylcarbonyl” (or “aralkylcarbonyl”) means the radical R—C(O)—,wherein R is an arylalkyl radical as defined herein. Examples ofarylalkylcarbonyl radicals include, but are not limited to,phenylacetyl, and the like.

“Heteroarylcarbonyl” means the radical R—C(O)—, wherein R is anheteroaryl radical as defined herein. Examples of heteroarylcarbonylradicals include, but are not limited to, pyridinoyl,3-methylisoxazoloyl, isoxazoloyl, thienoyl, furoyl, and the like.

“Heterocyclylcarbonyl” (or “heterocyclocarbonyl”) means the radicalR—C(O)—, wherein R is an heterocyclyl radical as defined herein.Examples of heterocyclylcarbonyl radicals include, but are not limitedto, piperazinoyl, morpholinoyl, pyrrolindinoyl, and the like.

“Cycloalkylcarbonyl” means the radical R—C(O)—, wherein R is acycloalkyl radical as defined herein. Examples of cycloalkylcarbonylradicals include, but are not limited to, cyclobutanoyl, cyclopentanoyl,cyclohexanoyl, and the like.

“Alkylaminocarbonyl” means the radical —C(O)NR′R″, wherein R′ is loweralkyl as defined herein, and R″ is hydrogen or lower alkyl as definedherein. Examples of alkylaminocarbonyl include, but are not limited tomethylaminocarbonyl, dimethylaminocarbonyl, t-butylaminocarbonyl,n-butylaminocarbonyl, iso-propylaminocarbonyl and the like.

“Arylaminocarbonyl” means the radical —C(O)NR′R″, wherein R′ is aryl asdefined herein, and R″ is hydrogen or aryl as defined herein. Examplesof arylaminocarbonyl include, but are not limited tophenylaminocarbonyl, methoxyphenylaminocarbonyl, diphenylaminocarbonyl,dimethoxyphenylaminocarbonyl, and the like.

“Heteroarylaminocarbonyl” means the radical —C(O)NR′R″, wherein R′ isheteroaryl as defined herein, and R″ is hydrogen or heteroaryl asdefined herein. Examples of heteroarylaminocarbonyl include, but are notlimited to pyridinylaminocarbonyl, thienylaminocarbonyl,furanylaminocarbonyl, and the like.

“Alkylcarbonylamino” means the radical —NC(O)R′, wherein R′ is loweralkyl as defined herein. Examples of alkylcarbonylamino include, but arenot limited to methylcarbonylamino, iso-propylcarbonylamino,t-butylcarbonylamino, and the like.

“Arylcarbonylamino” means the radical —NC(O)R′, wherein R′ is aryl asdefined herein. Examples of arylcarbonylamino include, but are notlimited to phenylcarbonylamino, tosylcarbonylamino, and the like.

“Alkylcarbamoyl” means the radical —OC(O)NR′R″, wherein R′ is loweralkyl as defined herein, and R″ is hydrogen or lower alkyl as definedherein. Examples of alkylcarbamoyl include, but are not limited tomethylcarbamoyl, ethylcarbamoyl, and the like.

“Arylcarbamoyl” means the radical —OC(O)NR′R″, wherein R′ is lower arylas defined herein, and R″ is hydrogen or aryl as defined herein.Examples of arylcarbamoyl include, but are not limited tophenylcarbamoyl, naphthylcarbamoyl, and the like.

“Arylalkylcarbamoyl” means the radical —OC(O)NHR′R″, wherein R′ is loweralkyl as defined herein, and R″ is aryl as defined herein. Examples ofarylalkylcarbamoyl include, but are not limited to benzylcarbamoyl,phenylethylcarbamoyl, and the like.

“Alkylaminosulfonyl” means the radical —S(O)₂NR′R″, wherein R′ is loweralkyl as defined herein, and R″ is hydrogen or lower alkyl as definedherein. Examples of alkylaminosulfonyl include, but are not limited tomethylaminosulfonyl, dimethylaminosulfonyl, and the like.

“Arylaminosulfonyl” means the radical —S(O)₂NR′R″, wherein R′ is aryl asdefined herein, and R″ is hydrogen or aryl as defined herein. Examplesof arylaminosulfonyl include, but are not limited tophenylaminosulfonyl, methoxyphenylaminosulfonyl, and the like.

“Heteroarylaminosulfonyl” means the radical —S(O)₂NR′R″, wherein R′ isheteroaryl as defined herein, and R″ is hydrogen or heteroaryl asdefined herein. Examples of heteroarylaminosulfonyl include, but are notlimited to thienylaminosulfonyl, piperidinylaminosulfonyl,furanylaminosulfonyl, imidazolylaminosulfonyl and the like.

“Alkylsulfonylamino” means the radical —NS(O)₂R′, wherein R′ is loweralkyl as defined herein. Examples of alkylsulfonylamino include, but arenot limited to methylsulfonylamino, propylsulfonylamino, and the like.

“Arylsulfonylamino” means the radical —NS(O)₂R′, wherein R′ is aryl asdefined herein. Examples of arylsulfonylamino include, but are notlimited to phenylsulfonylamino, naphthylsulfonylamino, and the like.

“Alkylsulfonyl” means the radical —S(O)₂R, wherein R is lower alkyl or asubstituted lower alkyl as defined herein. Examples of alkylsulfonylinclude, but are not limited to methylsulfonyl, trifluoromethylsulfonyl,propylsulfonyl, and the like.

“Arylsulfonyl” means the radical —S(O)₂R, wherein R is aryl as definedherein. Examples of arylsulfonyl include, but are not limited tophenylsulfonyl, nitrophenylsulfonyl, methoxyphenylsulfonyl,3,4,5-trimethoxyphenylsulfonyl, and the like.

“Heteroarylsulfonyl” means the radical —S(O)₂R, wherein R is heteroarylas defined herein. Examples of heteroarylsulfonyl include, but are notlimited to thienylsulfonyl, furanylsulfonyl, imidazolylsulfonyl,N-methylimidazolylsulfonyl and the like.

“Heterocyclylsulfonyl” means the radical —S(O)₂R, wherein R isheterocyclyl as defined herein. Examples of heterocyclylsulfonylinclude, but are not limited to piperidinylsulfonyl,piperazinylsulfonyl, and the like.

“Alkylsulfonyloxy” means the radical —O S(O)₂R, wherein R is lower alkylor substituted lower alkyl as defined herein. Examples ofalkylsulfonyloxy include, but are not limited to methylsulfonyloxy,trifluoromethylsulfonyloxy, propylsulfonyloxy, and the like.

“Arylsulfonyloxy” means the radical —O S(O)₂R, wherein R is aryl asdefined herein. Examples of arylsulfonyloxy include, but are not limitedto benzenesulfonyloxy., 4-chloro-benzenesulfonyloxy, and the like

“Heteroarylsulfonyloxy” means the radical —O S(O)₂R, wherein R ishetroaryl as defined herein. Examples of hetroarylsulfonyloxy include,but are not limited to thienylsulfonyloxy, and the like.

“Heterocyclylsulfonyloxy” means the radical —O S(O)₂R, wherein R isheterocycyl as defined herein. Examples of heterocyclylsulfohyloxyinclude, but are not limited to 3,5,dimethyl-isoxazolesulfonyloxy,pyrrolidinylsulfonyloxy, and the like

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optional bond” means that the bondmay or may not be present, and that the description includes single,double, or triple bonds.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under alkylating conditions. Examples of leavinggroups include, but are not limited to, halogen, alkyl- orarylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive oxygen atoms present in thereactants. Acceptable protective groups for alcoholic or phenolichydroxyl groups, which may be removed successively and selectivelyincludes groups protected as acetates, haloalkyl carbonates, benzylethers, alkylsilyl ethers, heterocyclyl ethers, and methyl or alkylethers, and the like. Protective or blocking groups for carboxyl groupsare similar to those described for hydroxyl groups, preferablytert-butyl, benzyl or methyl esters. Examples of protecting groups canbe found in T. W. Greene et al., Protective Groups in Organic Chemistry,(J. Wiley, 2^(nd) ed. 1991) and Harrison et al., Compendium of SyntheticOrganic Methods, Vols. 1-8 (J. Wiley and Sons 1971-1996).

“Amino-protecting group” means the protecting group that refers to thoseorganic groups intended to protect the nitrogen atom against undesirablereactions during synthetic procedures and includes, but is not limitedto, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ),p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. It ispreferred to use either BOC or CBZ as the amino-protecting group becauseof the relative ease of removal, for example by mild acids in the caseof BOC, e.g., trifluoroacetic acid or hydrochloric acid in ethylacetate; or by catalytic hydrogenation in the case of CBZ.

“Deprotection” or “deprotecting” means the process by which a protectivegroup is removed after the selective reaction is completed. Certainprotective groups may be preferred over others due to their convenienceor relative ease of removal. Deprotecting reagents for protectedhydroxyl or carboxyl groups include potassium or sodium carbonates,lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid,trifluoroacetic acid, palladium catalysts, or boron tribromide, and thelike.

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with one chiral center. It has twoenantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n-1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al.(1966) Angew. Chem. Inter. Edit., 5, 385; errata 511; Cahnet al. (1966) Angew. Chem., 78, 413; Cahn and Ingold (1951) J. Chem.Soc. (London), 612; Cahn et al. (1956) Experientia, 12, 81; Cahn, J.(1964) Chem. Educ., 41, 116).

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

“Atropic isomers” means the isomers owing their existence to restrictedrotation caused by hindrance of rotation of large groups about a centralbond.

“Substantially pure” means at least about 80 mole percent, morepreferably at least about 90 mole percent, and most preferably at leastabout 95 mole percent of the desired enantiomer or stereoisomer ispresent.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

(1) acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphthoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonicacid, propionic acid, salicylic acid, succinic acid,dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid,trimethylacetic acid, trifluoroacetic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicor inorganic base. Acceptable organic bases include diethanolamine,ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid,and phosphoric acid.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Crystal forms” (or polymorphs) means crystal structures in which acompound can crystallize in different crystal packing arrangements, allof which have the same elemental composition. Different crystal formsusually have different X-ray diffraction patterns, infrared spectra,melting points, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate. “Prodrug” means a pharmacologicallyinactive form of a compound which must be metabolized in vivo, e.g., bybiological fluids or enzymes, by a subject after administration into apharmacologically active form of the compound in order to produce thedesired pharmacological effect. The prodrug can be metabolized beforeabsorption, during absorption, after absorption, or at a specific site.Although metabolism occurs for many compounds primarily in the liver,almost all other tissues and organs, especially the lung, are able tocarry out varying degrees of metabolism. Prodrug forms of compounds maybe utilized, for example, to improve bioavailability, improve subjectacceptability such as by masking or reducing unpleasant characteristicssuch as bitter taste or gastrointestinal irritability, alter solubilitysuch as for intravenous use, provide for prolonged or sustained releaseor delivery, improve ease of formulation, or provide site-specificdelivery of the compound. Prodrugs are described in The OrganicChemistry of Drug Design and Drug Action, by Richard B. Silverman,Academic Press, San Diego, 1992. Chapter 8: “Prodrugs and Drug deliverySystems” pp.352-401; Design of Prodrugs, edited by H. Bundgaard,Elsevier Science, Amsterdam, 1985; Design of BiopharmaceuticalProperties through Prodrugs and Analogs, Ed. by E. B. Roche, AmericanPharmaceutical Association, Washington, 1977; and Drug Delivery Systems,ed. by R. L. Juliano, Oxford Univ. Press, Oxford, 1980.

“Subject” means mammals and non-mammals. Mammals means any member of theMammalia class including, but not limited to, humans, non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,and disease state being treated, the severity or the disease treated,the age and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

“Pharmacological effect” as used herein encompasses effects produced inthe subject that achieve the intended purpose of a therapy. In onepreferred embodiment, a pharmacological effect means that primaryindications of the subject being treated are prevented, alleviated, orreduced. For example, a pharmacological effect would be one that resultsin the prevention, alleviation or reduction of primary indications in atreated subject. In another preferred embodiment, a pharmacologicaleffect means that disorders or symptoms of the primary indications ofthe subject being treated are prevented, alleviated, or reduced. Forexample, a pharmacological effect would be one that results in theprevention or reduction of primary indications in a treated subject.

“Disease state” means any disease, condition, symptom, or indication.

“Treating” or “treatment” of a disease state includes:

(1) preventing the disease state, i.e. causing the clinical symptoms ofthe disease state not to develop in a subject that may be exposed to orpredisposed to the disease state, but does not yet experience or displaysymptoms of the disease state;

(2) inhibiting the disease state, i.e., arresting the development of thedisease state or its clinical symptoms; or

(3) relieving the disease state, i.e., causing temporary or permanentregression of the disease state or its clinical symptoms.

“Antagonist” means a molecule such as a compound, a drug, an enzymeinhibitor, or a hormone, that diminishes or prevents the action ofanother molecule or receptor site.

“Disorders of the urinary tract” or “uropathy” used interchangeably with“symptoms of the urinary tract” means the pathologic changes in theurinary tract. Symptoms of the urinary tract include overactive bladder(also known as detrusor hyperactivity), outlet obstruction, outletinsufficiency, and pelvic hypersensitivity.

“Overactive bladder” or “Detrusor hyperactivity” includes, but is notlimited to, the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, and the like; and the symptoms usuallymanifested in detrusor hyperreflexia (neurogenic bladder), in conditionssuch as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

“Outlet obstruction” includes, but is not limited to, benign prostatichypertrophy (BPH), urethral stricture disease, tumors and the like. Itis usually symptomatically manifested as obstructive (low flow rates,difficulty in initiating urination, and the like), or irritative(urgency, suprapubic pain, and the like).

“Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, or mixed incontinence.It is usually symptomatically manifested as stress incontinence.

“Pelvic Hypersensitivity” includes but is not limited to, pelvic pain,interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia,urethritis, orchidalgia, and the like. It is symptomatically manifestedas pain, inflammation or discomfort referred to the pelvic region, andusually includes symptoms of overactive bladder.

Nomenclature

The naming of the compounds of this invention is illustrated below:

In general, the nomenclature used in this Application is based onAUTONOM™, a Beilstein Institute computerized system for the generationof IUPAC systematic nomenclature. A compound of Formula I wherein R¹ andR² are methoxy, R³ is propyl, p is 2, n is 3, m is 2, X and Y are CH₂and Z is NH is named:4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one.

Preferred Compounds

Among compounds of the present invention set forth in the Summary of theInvention, certain compounds of Formula I, or prodrugs, individualisomers, racemic or non-racemic mixtures of isomers, or pharmaceuticallyacceptable salts or solvates thereof, are preferred:

R¹, and R² are independently in each occurrence preferably hydrogen,halogen, (C₁₋₆)-alkyl, alkoxy, alkylsulfonyl, or alkylsulfonyloxy, andmore preferably hydrogen, methoxy, methylsulfonyl, or methylsulfonyloxy.

R³ is independently in each occurrence preferably lower alkyl, loweralkenyl or lower alkynyl, more preferably ethyl, propyl, iso-propyl,allyl or propargyl, and even more preferably ethyl or propyl.

p is preferably 1 to 3, more preferably 1 to 2, and even more preferably2.

m is preferably 0 to 3; more preferably 1 to 2; and even more preferably2.

n is preferably 1 to 6; more preferably 1 to 3; and even more preferably3.

one of X, Y, or Z is independently in each occurrence preferably S, O,or NR⁴, most preferably NR⁴, and even more preferably NH.

Other preferred compounds of the present invention include thepharmaceutically acceptable salts of the compounds of the presentinvention wherein the pharmaceutically acceptable salts are formed fromhydrochloric acid, 2,2,2-trifluoroacetic acid, dibenzoyl-L-tartaricacid, sodium, or phosphoric acid, more preferably the salts are formedfrom hydrochloric acid, 2,2,2-trifluoroacetic acid.

Exemplary particularly preferred compounds, or prodrugs, individualisomers, racemic or non-racemic mixtures of isomers, or pharmaceuticallyacceptable salts or solvates thereof, include:

3,5-dimethyl-isoxazole-4-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester;

4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one;

4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one;

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;

1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;or

3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one.

General Synthetic Reaction Schemes

Compounds of the present invention may be made by the methods depictedin the illustrative synthetic reaction schemes shown and describedbelow.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser (1991) Reagents for Organic Synthesis; Wiley & Sons: NewYork, Volumes 1-15; Rodd (1989) Chemistry of Carbon Compounds, ElsevierScience Publishers, Volumes 1-5 and Supplementals; and (1991) OrganicReactions, Wiley & Sons: New York, Volumes 1-40. The following syntheticreaction schemes are merely illustrative of some methods by which thecompounds of the present invention may be synthesized, and variousmodifications to these synthetic reaction schemes may be made and willbe suggested to one skilled in the art having referred to the disclosurecontained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes may be isolated and purified if desired using conventionaltechniques, including but not limited to filtration, distillation,crystallization, chromatography, and the like. Such materials may becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably take place at atmospheric pressure over a temperature rangefrom about −78° C. to about 150° C., more preferably from about 0° C. toabout 125° C., and most preferably and conveniently at about room (orambient) temperature, e.g., about 20° C.

Scheme A

Scheme A, in general, describes a method of preparing a compound ofFormula I wherein X, Y, Z, R¹, R², R³, p, m, and n are as described inthe Summary of the Invention.

A compound of Formula I can generally be prepared by coupling acarboxaldehyde 1 with a benzocyclylamine 2 under reductive aminationconditions. Suitable reducing conditions include sodiumtriacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxideand sodium cyanoborohydride, hydrogen and a metal catalyst and hydrogentransfering agents such as cyclohexene, formic acid and its salts, zincand hydrochloric acid, formic acid, or borane dimethylsulfide followedby treatment with formic acid. Suitable inert organic solvents for thereaction include dichloromethane, 1,2-dichloroethane, tetrahydrofuran,alcohols, or ethyl acetate, and the like. Preferably the reaction iscarried out under basic conditions with sodium triacetoxyborohydride in1,2-dichloroethane.

Reductive amination procedures are described in the chemical literature.For example, (1996) J. Org. Chem., 61, 3849 and (1996) TetrahedronLetters, 37, 3977, describe methods utilizing sodiumtriacetoxyborohydride as a reagent for the reductive amination ofaldehydes with a wide variety of amines. For example, (1971) J. Am.Chem. Soc., 93, 2897 and (1988) Org. Synth. Coll., 6, 499 describemethods utilizing sodium cyanoborohydride as reagent for reductiveamination of carbonyl compounds.

The conventional starting materials of Scheme A are commerciallyavailable or are known to, or can readily be synthesized by those ofordinary skill in the art. For example, the starting carboxaldehyde 1can readily be synthesized as shown by the following reaction schemes(1), (2), and (3):

A carboxaldehyde 1 wherein X, Y, Z, m, and n are as described in theSummary of the Invention can be prepared by reacting the amido group ofcompound a with an alkylating agent of the formula L(CH₂)_(n)CH═CH₂wherein L is a leaving group such as halogen or methanesulfonyloxy,preferably chloro, under basic conditions to obtain a compound b. Thealkylation reaction is followed by the oxidation/cleavage of theterminal alkene group of compound b to an aldehyde group to obtain acarboxaldehyde 1. Various oxidizing agents used in theoxidation/cleavage of alkenes to aldehydes are described in the chemicalliterature. For example, (1956) J. Org. Chem., 21, 478 describes methodsutilizing osmium tetroxide and sodium (meta)periodate; (1982) Syn.Comm., 12, 1063 describes methods utilizing potassium permanganate andsodium(meta)periodate; (1987) J. Org. Chem., 52, 3698 describes methodsutilizing potassium permanganate and silica gel; (1958) Chem. Rev., 58,925 describes methods utilizing ozone; (1986) J. Org. Chem., 51, 3213describes methods utilizing potassium permanganate alone; (1987) J. Org.Chem., 52, 2875 describes methods utilizing sodium (meta)periodate andcatalytic ruthenium. Preferably the reaction is carried out with osmiumtetroxide and sodium (meta)periodate or ozone.

Alternatively, a carboxaldehyde 1 wherein X, Y, Z, m, and n are asdescribed in the Summary of the Invention can be prepared by reactingthe free amine group of compound a with an alkylating agent of theformula L(CH₂)_(n)C(OR)₂ wherein R is lower alkyl and L is a leavinggroup such as halogen, preferably bromo, to obtain a compound c. Thealkylation reaction is followed by the hydrolysis of the acetal group ofcompound c under acidic conditions to obtain a carboxaldehyde 1.

Alternatively, a carboxaldehyde 1 wherein X, Y, Z, m, and n are asdescribed in the Summary of the Invention, can be prepared by treatingan aminoacetal d wherein R is lower alkyl with an appropriate acylatingagent such as acylating agents of the formula L(CH₂)_(n)COL′, orL(CH₂)_(n)OCOL′, or L(CH₂)_(n)N═C═O wherein in each instance L′ is aleaving group such as halogen, preferably chloro, to obtain compound e.The acylating reaction is followed by the internal N-alkylation ofcompound e, and the subsequent hydrolysis of the acetal group ofcompound f to obtain a carboxaldehyde 1.

For example, the starting benzocyclylamine 2 can be synthesized as shownby the following reaction scheme (4):

A benzocyclylamine 2 wherein R¹, R², and R³, are as described in theSummary of the Invention may be prepared by treatment of abenzocyclylone g with a primary amine of the formula R³NH₂ underreductive amination conditions. Various methods for the synthesis of abenzocyclylamine 2 are described in the chemical literature, forexample, (1980) J. Med. Chem., 23, 745-749; (1981) J. Med. Chem., 24,429-434; (1989) J. Med. Chem., 32, 2128-2134, (1996) J. Org. chem., 61,3849-3862. and (1997) Bioorg.Med Chem.Lett., 15, 1995-1998.

Scheme B

Scheme B, in particular, describes a method of preparing a compound ofFormula I wherein X is NR⁴, O, or S; Y and Z are each CH₂; and R¹, R²,R³, R⁴, p, m, and n are as described in the Summary of the Invention.

A compound of Formula IB can be prepared by proceeding as described inScheme A. Preferably, a compound of Formula IB can be prepared byreacting a carboxaldehyde 1b with a benzocyclylamine 2 under reductiveamination conditions as described in Scheme A.

Exemplary preparations of a compound of Formula IB are given in Example1.

Scheme C

Scheme C, in particular, describes a method of preparing a compound ofFormula I wherein X and Z are each CH₂, Y is NR⁴, O or S, and R¹, R²,R³, R⁴, p, m, and n are as described in the Summary of the Invention.

A compound of Formula IC can be prepared by proceeding as described inScheme A.

Preferably, a compound of Formula I wherein Y is O or S can be preparedby reacting a carboxaldehyde 1c with a benzocyclylamine 2 underreductive amination conditions as described in Scheme A.

Alternatively, a compound of Formula I wherein Y is NR⁴ can also beprepared by coupling a nitrogen-protected carboxaldehyde 1 d wherein Pis a suitable nitrogen-protecting group with a benzocylcylamine 2 inconditions as described above. This reaction is followed by removing thenitrogen-protecting group of compound 3 under acidic conditions toobtain a compound of Formula I wherein Y is NH. The compound of FormulaI wherein Y is NH may then be further reacted with an appropriatealkylating agent, acylating agent, or sulfonylating agent by proceduresknown to one skilled in the art to obtain a compound of Formula Iwherein Y is NR⁴ wherein R⁴ is other than H.

Exemplary preparations of a compound of Formula IC are given in Examples2, 3, and 4.

Scheme D

Scheme D, in particular, describes a method of preparing a compound ofFormula I wherein X and Y are each CH₂, and Z is NR⁴, O or S, and R¹,R², R³, R⁴, p, m, and n are as described in the Summary of theInvention.

A compound of Formula ID can be prepared by proceeding as described inScheme A.

Preferably, a compound of Formula I wherein Z is O or S can be preparedby reacting a carboxaldehyde 1e with a benzocyclylamine 2 underconditions as described in Scheme A.

Alternatively, a compound of Formula I wherein Z is NR⁴ can be preparedby coupling an amino-protected carboxaldehyde 1f wherein P is a suitablenitrogen-protecting group with a benzocyclylamine 2 as mentioned above.This reaction is followed by removing the nitrogen-protecting group ofcompound 4 under acidic conditions to obtain a compound of Formula Iwherein Z is NH. Optionally the compound of Formula I wherein Z is NHmay then be further reacted with an appropriate alkylating agent,acylating agent, or sulfonylating agent by procedures known to oneskilled in the art to obtain a compound of Formula I wherein Z is NR⁴wherein R⁴ is other than H.

Exemplary preparations of a compound of Formula ID are given in Examples5, 6, and 7.

General Utility

Compounds that act as antagonists of muscarinic receptors have been usedto treat several disease states associated with improper smooth musclefunction. Until recently, most of these compounds have beennon-selective for the various muscarinic receptor subtypes, leading tounpleasant anti-cholinergic side-effects such as dry mouth,constipation, blurred vision or tachycardia, the most common of which isdry-mouth that results from muscarinic receptor blockade in the salivarygland. Recently developed M2 or M3 specific antagonists have been shownto have reduced side effects. Evidence suggests that concurrent blockadeof M2 and M3 receptors could be therapeutically effective in thetreatment of disease states associated with smooth muscle disorders,such as genitourinary tract disorders, respiratory tract disorders,gastrointestinal tract disorders, and smooth muscle disorders.

Genitourinary tract disorders treatable with compounds of this inventionspecifically include overactive bladder or detrusor hyperactivity andits symptoms such as the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, and the like; and the symptoms usuallymanifested in detrusor hyperreflexia (neurogenic bladder), in conditionssuch as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

Gastrointestinal tract disorders treatable with compounds of thisinvention specifically include irritable bowel syndrome, diverticulardisease, achalasia, gastrointestinal hypermotility disorders, anddiarrhea. Respiratory tract disorders treatable with compounds of thisinvention specifically include chronic obstructive pulmonary disease,asthma and pulmonary fibrosis.

These and other therapeutic uses are described, for example, in Goodman& Gilman, (1996) The Pharmacological Basis of Therapeutics, ninthedition, McGraw-Hill, New York, Chapter 26:601-616; and Coleman, R. A.,(1994) Pharmacological Reviews, 46:205-229.

Testing

The compounds of this invention are muscarinic receptor antagonists. Themuscarinic receptor affinity of test compounds can be determined by anin vitro receptor binding assay which utilizes a cell membranepreparation from the Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (M₁-M₅), and is described in moredetail in Example 15.

The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated saliva secretion in anesthetizedrats, and is described in more detail in theOxotremorine/Pilocarpine-induced salivation (OIS/PIS) model inanesthetized rats, Example 16.

The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction in anesthetizedrats, and is described in more detail in the inhibition ofvolume-induced contractions assay, Example 17.

The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction and salivasecretion in anesthetized dogs, and is described in more detail inExample 18.

Administration and Pharmaceutical Composition

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or a prodrug, an individualisomer, a racemic or non-racemic mixture of isomers or apharmaceutically acceptable salt, or solvate thereof together with atleast one pharmaceutically acceptable carrier, and optionally othertherapeutic and/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease. In general, compounds of the presentinvention will be administered as pharmaceutical formulations includingthose suitable for oral (including buccal and sublingual), rectal,nasal, topical, pulmonary, vaginal, or parenteral (includingintramuscular, intraarterial, intrathecal, subcutaneous and intravenous)administration or in a form suitable for administration by inhalation orinsufflation. The preferred manner of administration is generally oralusing a convenient daily dosage regimen which can be adjusted accordingto the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

The compounds of the present invention can be formulated in transdermalor subcutaneous drug delivery devices. These delivery systems areadvantageous when sustained release of the compound is necessary andwhen patient compliance with a treatment regimen is crucial. Compoundsin a transdermal delivery systems are frequently attached to askin-adhesive solid support. The compound of interest can also becombined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington, (1995) The Science and Practice of Pharmacy(1995), edited by E. W. Martin, Mack Publishing Company, 19th edition,Easton, Pa. Representative pharmaceutical formulations containing acompound of the present invention are described in Examples 9-15.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Preparation 1 Preparation of a Compound of Formula 14-(5-oxo-[1,4]oxazepan-4-yl)-butyraldehyde

To a stirred suspension of sodium hydride (0.9 g, 37.5 mmole) indimethylformamide (50 mL) was added 1,4-oxazepan-2-one (30 mmole). Themixture was stirred at room temperature for 15 minutes, and then5-bromo-1-pentene (5.03 g, 33.7 mmole) was added slowly. The reactionmixture was stirred at room temperature for 30 minutes, and then at 80°C. for 16 hours. The solvent was removed under reduced pressure andwater was added to the residue. The mixture was extracted with diethylether, the organic phase was washed with water, dried (magnesiumsulfate) and concentrated to give 1-pent-4-enyl-oxazepan-2-one (5.5 g,)as an oil.

Osmium tetroxide (17 mg, 0.07 mmole) was added to1-pent-4-enyl-oxazepan-2-one (5.5 g, 28.3 mmole) in a mixture oftetrahydrofuran (100 mL) and water (50 mL) under ambient water bathcooling. The mixture was stirred for 5 minutes and solid sodiumperiodate (15.11 g, 70.65 mmole) was added in portions over 15 minutes.The reaction mixture was stirred for 3 hours and filtered. The filtratewas concentrated, saturated with solid sodium chloride, and extractedwith methylene chloride. The organic phase was dried (magnesium sulfate)and concentrated. Purification by silica gel chromatography, elutingwith chloroform, gave 4-(2-oxo-oxazepan-1-yl)-butyraldehyde (4.6 g).

Similarly, following the procedure described above in Preparation 1, butoptionally replacing 1,4-oxazepan-2-one with other appropriate compoundsof formula a and optionally replacing 5-bromo-1-pentene with otherappropriate alkylating agents of the formula L(CH₂)_(n)CH═CH₂ wherein Lis a leaving group such as halogen, and utilizing modifications known tothose skilled in the art, the additional compounds of formula 1 wereprepared:

5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester.

Preparation 2 Alternative Preparation of a Compound of Formula 15-Oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester

To a suspension of 60% sodium hydride in mineral oil (0.2 g, 5 mmole) inN,N-dimethylformamide (6 mL) was added 5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester (1.0 g, 4.67 mmole). The reaction mixture waswarmed at 50° C. for 5 minutes, and then at room temperature for 15minutes. To the resulting solution was added 4-bromobutyraldehydedimethyl acetal (0.99 g, 5 mmole). After the reaction mixture wasstirred at room temperature for 16 hours, the solvent was removed, andthe residue was partitioned between water and ethyl acetate. The organicphase was washed with water, dried (magnesium sulfate), andconcentrated. The residue was dissolved in diethyl ether, and thesuspension was filtered, and the filtrate was concentrated. Purificationby silica gel chromatography, eluting with 2% methanol in chloroform,gave 4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylic acidtert-butyl ester (0.8 g,) as a heavy syrup. Nmr: (chloroform-d) δ (ppm)1.49, s, (9H); 2.64, m, 3H; 3.32, s (3H); 4.37, m, (1H).

A solution of 4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester (3 g, 9.08 mmole) in glacial acetic acidcontaining 0.5 mL water (10 mL) was stirred at room temperature for 24hours. The solution was concentrated at 35° C. under reduced pressure,and the residue was partitioned between saturated aqueous sodiumbicarbonate and diethyl ether. The organic phase was dried (magnesiumsulfate), concentrated, and the residue recrystallized from diethylether/hexane to give 5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.85 g,), m.p. 86-87° C.

Preparation 3 Alternative Preparation of Compounds of Formula 1

To an ice-cooled solution of 1.93M phosgene in toluene (31 mL, 60 mmole)was added dropwise a solution of 5-chloro-1-pentanol (4.9 g, 40 mmole)and N,N-diethylaniline (5.97 g, 40 mmole) in toluene (40 mL). Thereaction mixture was stirred at ambient temperature for 4 hours. Themixture was filtered, and the filtrate was concentrated. The residue wastaken up in ethyl acetate, filtered, and the solution was added dropwiseto an ice-cooled solution of 4-aminobutyraldehyde diethylacetal (7.09 g,44 mmole) and triethylamine (4.45 g, 44 mmole) in ethyl acetate (60 mL).The reaction mixture was stirred at room temperature for 15 hours,filtered and concentrated. Purification by silica gel chromatography,eluting with 10% ethyl acetate in hexane, gave(4,4-diethoxybutyl)carbamic acid 5-chloro-pentyl ester (11.4 g,) as anoil.

To a solution of (4,4-diethoxybutyl)carbamic acid 5-chloro-pentyl ester(11.4 g, 44 mmole) dissolved in N,N-dimethylformamide (100 mL) was addedde-oiled sodium hydride (1.01 g, 42.3 mmole). The reaction mixture wasstirred for 15 hours at room temperature, and then at 70° C. for 3hours. The mixture was diluted with water, saturated aqueous sodiumchloride was added, and extracted with diethyl ether. The organic phasewas washed with water, dried (magnesium sulfate), and concentrated.Purification by silica gel chromatography, gave3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2.03 g) as a viscous oil.

A mixture of 3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2 g, 7.3 mmole)and 1.5 g Dowex 50W2-200 ion exchange resin in 3% aqueoustetrahydrofuran (30 mL) was heated under reflux for 24 hours. Themixture was filtered, and the filtrate was concentrated and dissolved indichloromethane. The solution was dried with magnesium sulfate andconcentrated to give 4-(2-oxo-[1,3]oxazocan-3-yl)-butyraldehyde (1.45 g)as a viscous oil which solidified.

3-(2-Oxo-tetrahydropyrimidin-1-yl)-propionaldehyde

To a stirred and ice-cooled solution of 3-aminopropionaldehydediethylacetal (5.88 g, 40 mmole) in diethyl ether (35 mL) was addeddropwise 3-chloropropyl isocyanate (4.78 g, 40 mmole). The reactionmixture was stirred at room temperature for 4 hours. The mixture wasconcentrated and dissolved in N,N-dimethylformamide (40 mL). To thissolution was added de-oiled sodium hydride (0.96 g, 40 mmole). Thereaction mixture was stirred at 70° C. for 18 hours, concentrated, takenup in diethyl ether (40 mL), and filtered. The filtrate was concentratedand purified by silica gel chromatography, eluting with hexane-ethylacetate-methanol (10:9.7:0.3), gave1-(3,3-diethoxypropyl)-tetrahydropyrimidin-2-one (9.05 g) as an oil.

A mixture of 1-(3,3-diethoxypropyl)-tetrahydropyrimidin-2-one (1 g, 4.35mmole), and 1.0 g Dowex 50W2-200 ion exchange resin in 3% aqueoustetrahydrofuran (30 mL) was heated under reflux for 24 hours. Themixture was filtered, the filtrate was concentrated and the residuedissolved in dichloromethane (30 mL), dried with magnesium sulfate, andconcentrated to give 3-(2-oxo-tetrahydropyrimidin-1-yl)-propionaldehyde(0.46 g).

Preparation 4 Preparation of a Compound of Formula 2 (R¹, R²═H,R³=propyl, p=2) Propyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine

To a solution of 3,4-dihydro-1-H-naphthalen-2-one (5 g, 34 mmol) in1,2-dichloroethane (250 mL), propyl amine (2.8 mL, 34 mmol) was added,followed by addition of sodium triacetoxyborohydride (22 g, 102 mmol).The reaction was stirred at ambient temperature under nitrogen for 24hours, at which time it was concentrated in vacuo. The remaining solidwas partitioned between 1M sodium hydroxide and ethyl acetate. The ethylacetate was washed with brine, dried over magnesium sulfate, andfiltered. The filtrate was acidified with 1 M HCl in ether and 6.3 g ofpropyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine was collected as apale pink precipitate.

Example 1 Preparation of a Compound of Formula IB as Described in SchemeB3-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one(19)

To a solution of 7-Methoxy-3,4-dihydro-1-H-naphthalen-2-one (5.0 g, 28.4mmol) and propylamine (2.8 mL, 34 mmol, 1.2 eq) in 1,2-dichloroethane(150 mL) under inert atmosphere was added sodium triacetoxyborohydride(15 g, 71 mmol, 2.5 eq) in a single portion. The reaction was allowed tostir at room temperature for 20 h then concentrated in-vacuo. Theresidue was partitioned between 10% aq. KOH (150 mL) and ethyl acetate(75 mL). The organic layer was washed with brine, dried andconcentrated. The resulting material was dissolved in diethyl ether (100mL) and treated with 1M HCl in ether (28.4 ML). The solid was collectedand dried under vacuum to afford 6.23 g of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl-propyl-amine ashydrochloride salt.

To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca.13 mg50 umole), was added 440 μL solution of4-(2-oxo-[1,3]oxazinan-3-yl)-butyraldehyde (0.125 M in 1,2dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 Mslurry of sodium triacetoxyborohydride in 1,2 dichloroethane. Thereaction was shaken at room temperature for 48 h. After quenching with 2mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL waterand ethyl acetate to workup flasks. The organic phase was washed, driedand concentrated. Purification by chromatography yielded3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one19, MS: 375 ([M+H]⁺).

Similarly, following the procedure described above in Example 1, butoptionally replacing 4-(2-oxo-[1,3]oxazinan-3-yl)-butyraldehyde withother appropriate compounds of formula 1b and optionally replacing7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinX is O, were prepared as trifluoroacetic acid salts:

3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one20, MS: 389 ([M+H]⁺);

3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one28, MS: 419 ([M+H]⁺);

3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one29, MS: 405 ([M+H]⁺);3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazocan-2-one31, MS: 403 ([M+H]⁺);

3-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one57, MS: 381 ([M+H]⁺);

3-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one58, MS: 395 ([M+H]⁺);

3-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazocan-2-one60, MS: 409 ([M+H]⁺);

3-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one69, MS: 404 ([M+H]⁺);

3-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one70, MS: 390 ([M+H]⁺);

3-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one118, MS: 389 ([M+H]⁺);

3-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one145, MS: 403 ([M+H]⁺);

3-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one147, MS: 389 ([M+H]⁺);

3-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one161, MS: 425 ([M+H]⁺);

3-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one162, MS: 439 ([M+H]⁺); or

3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one174, MS: 419 ([M+H]⁺).

Example 2

Preparation of a Compound of Formula IC as Described in Scheme C

1-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one(3)

To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-aminehydrochloride prepared as described in Example 1 (500 mg, 2 mmol, 1 eq)and triethylamine (0.3 mL, 2.2 mmol, 1.1 eq.) in 1,2-dichlororethane (20mL) under inert atmosphere was added the3-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester(550 mg, 2 mmol, 1 eq.) in a single portion followed by the sodiumtriacetoxyborohydride (650 mg, 3 mmol, 1.5 eq.). The reaction wasstirred at room temperature for 20 hr, concentrated in-vacuo and thenpartitioned between 10% KOH (40 mL) and ethyl acetate (75 mL), theorganic layer was washed with brine, dried (MgSO₄) and concentrated.Purification by chromatography provided 858 mg of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester.

To a solution of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester (858 mg, 1.64 mmol) in methylene chloride (25 mL)was added trifluoroacetic acid (5 mL) in a single portion, and thereaction was stirred at room temperature for 30 min. The mixture wasconcentrated to dryness in-vacuo, dissolved in water and treated with15% aq. KOH The solution was extracted with ethyl acetate, washed withbrine, dried (MgSO₄) and concentrated to dryness. The free base (682 mg,1.7 mmol) was taken up in diethyl ether (30 mL) and treated with 1MHCl/ether (3.4 mL). The solid was collected and dried under vacuum toafford the product 3 as a dihydrochloride (767 mg, 98% yield), MS 374([M+H]⁺).

Similarly, following the procedures described above in Example 2, butoptionally replacing 3-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester with other appropriate compounds of formula 1d andoptionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinY is NH were prepared:

1-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one1, MS: 388 ([M+H]⁺);

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one12, MS: 374 ([M+H]⁺);

1-{4-[ethyl-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-butyl}-[1,4]diazepan-2-one15, MS: 374 ([M+H]⁺);

1-{3-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-propyl}-[1,4]diazepan-2-one23, MS: 374 ([M+H]⁺);

1-{4-[(7-methanesulfonyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one25, MS: 418 ([M+H]⁺);

1-{4-[(7-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one36, MS: 402 ([M+H]⁺);

1-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one54, MS: 480 ([M+H]⁺);

1-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one63, MS: 394 ([M+H]⁺);

1-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one72, MS: 403 ([M+H]⁺);

1-{3-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-propyl}-[1,4]diazepan-2-one74, MS: 389 ([M+H]⁺);

1-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one89, MS: 374 ([M+H]⁺);

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one91, MS: 374 ([M+H]⁺);

1-{4-[(R)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one92, MS: 388 ([M+H]⁺);

1-{4-[(S)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one93, MS: 388 ([M+H]⁺);

1-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one111, MS: 388 ([M+H]⁺);

1-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one112, MS: 402 ([M+H]⁺);

1-{4-[(6-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one114, MS: 402 ([M+H]⁺);

1-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one148, MS: 388 ([M+H]⁺);

1-{5-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-piperazin-2-one154, MS: 418([M+H]⁺);

1-{5-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-2-one155, MS: 432([M+H]⁺);

1-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one156, MS: 418([M+H]⁺);

1-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one166, MS: 404([M+H]⁺);

1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one171, MS: 436([M+H]⁺); or

1-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one173, MS: 418([M+H]⁺).

Example 3 Alternative Preparation of a Compound of Formula IC asDescribed in Scheme C4-(2-Dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one(64)

To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-aminehydrochloride (150 mg, 0.3 mmol) and triethylamine (0.2 mL, 1.3 mmol) inmethylene chloride (10 mL) under inert atmosphere was added2-chloroethane sulfonyl chloride (0.03 mL, 0.3 mmol). The reactionmixture was allowed to stir at room temperature for 1 hour, and wasquenched with 2% sodium carbonate. The organic layer was dried (MgSO₄),filtered and concentrated in-vacuo to afford4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-sulfonylchloride as a yellow oil.

To4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-sulfonylchloride (0.3 mmol) and triethylamine (0.1 mL, 0.6 mmol,) in methylenechloride (15 mL) under inert atmosphere was added dimethyl amine 2 M inTHF (0.17 mL, 0.34 mmol). The reaction was allowed to stir at roomtemperature for 20 h, then concentrated in-vacuo. The remaining oil waspurified over silica gel to afford a clear oil which was taken up indiethyl ether (10 mL) and treated with 1M HCl in ether. The solid wascollected and dried under vacuum to afford4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-oneas a dihydrochloride (83 mg) 64, MS: 523([M+H]⁺).

Similarly, following the procedures described above in Example 3, butoptionally replacing1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-onewith other free amine compounds of Formula IC, and optionally replacing2-chloroethane sulfonyl chloride with other appropriate acylating,alkylating, or sulfonylating agents, and utilizing modifications knownto those skilled in the art, the additional compounds of Formula Iwherein Y is NR⁴ were prepared:

4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one2, MS: 523([M+H]⁺);

4-(4-fluoro-benzoyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one121, MS: 496([M+H]⁺);

4-(2,2-dimethyl-propionyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one122, MS: 458([M+H]⁺);

4-isobutyryl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one123, MS: 444([M+H]⁺);

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-(thiophene-2-carbonyl)-piperazin-2-one124, MS: 484([M+H]⁺);

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid diethylamide 125, MS: 473([M+H]⁺);

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid dimethylamide 126, MS: 445([M+H]⁺);

4-acetyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one127, MS: 416([M+H]⁺);

4-(3,5-dimethyl-isoxazole-4-carbonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one128, MS: 497([M+H]⁺);

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-(thiophene-2-sulfonyl)-piperazin-2-one129, MS: 520([M+H]⁺);

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-trifluoromethanesulfonyl-piperazin-2-one130, MS: 506([M+H]⁺);

4-benzenesulfonyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one131, MS: 514([M+H]⁺);

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-sulfonicacid dimethylamide 132, MS: 481 ([M+H]⁺);

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid phenylamide 133, MS: 493([M+H]⁺);

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid ter-butylamide 134, MS: 473([M+H]⁺);

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid methylamide 135, MS: 431 ([M+H]⁺);

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-thiophen-2-ylmethyl-piperazin-2-one136, MS: 470([M+H]⁺);

4-ethyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one137, MS: 470([M+H]⁺);

4-(1-methanesulfonyl-piperidin-4-ylmethyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one138, MS: 549([M+H]⁺); or

4-methanesulfonyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one139, MS: 452([M+H]⁺).

Example 4 Alternative Preparation of a Compound of Formula IC asDescribed in Scheme C4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one(17)

To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca. 13mg 50 μmole) as described in Example 1, was added 440 μL solution of4-(2-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.125 M in 1,2dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 Mslurry of sodium triacetoxyborohydride in 1,2 dichloroethane. Thereaction was shaken at room temperature for 48 h. After quenching with 2mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL waterand ethyl acetate to workup flasks. The organic phase was washed, driedand concentrated. Purification by chromatography yielded4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one17, MS: 389([M+H]⁺);

Similarly, following the procedure described above in Example 4, butoptionally replacing 4-(2-oxo-[1,4]oxazepan-4-yl)-butyraldehyde withother appropriate compounds of formula 1c and optionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinY is O:

4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one27, MS: 419([M+H]⁺);

4-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one55, MS: 395([M+H]⁺);

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-(morpholine-4-carbonyl)-piperazin-2-one120, MS: 487([M+H]⁺); or

4-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one144, MS: 403([M+H]⁺).

Example 5 Preparation of a Compound of Formula ID as Described in SchemeD4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one(5)

To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine prepared asdescribed in Example 1 (800 mg, 3.3 mmol, 1 eq) in 1,2-dichlororethane(40 mL) under inert atmosphere was added5-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester(1.0 g, 3.6 mmol, 1.1 eq.) in a single portion followed by the sodiumtriacetoxyborohydride (1.7 g, 8.25 mmol, 2.5 eq.). The reaction wasstirred at room temperature for 20 hr, concentrated in-vacuo and thenpartitioned between 10% KOH (50 mL) and ethyl acetate (100 mL). Theorganic layer was washed with brine, dried (MgSO₄) and concentrated.Purification by silica gel chromatography gave 1.1 g of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester.

To4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester (800 mg, 1.64 mmol) in methylene chloride (15 mL)was added trifluoroacetic acid (5 mL) in a single portion and thereaction was stirred at room temperature for 30 min. The mixture wasconcentrated to dryness in-vacuo, dissolved in water (40 mL) and treatedwith 15% aq. KOH (20 mL). The solution was extracted with ethyl acetate,washed with brine, dried (MgSO₄) and concentrated in-vacuo. The freebase (636 mg, 1.64 mmol) was taken up in diethyl ether (30 mL) andtreated with 1M HCl in ether (3.3 mL). The solid was collected and driedunder vacuum to afford 732 mg of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one5 as a dihydrochloride salt. MS: 374([M+H]⁺).

Similarly, following the procedures described above in Example 5, butoptionally replacing 5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester with other appropriate compounds of formula 1f andoptionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinZ is NH were prepared:

4-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one4, MS: 388([M+H]⁺);

N-(2-{ethyl-[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-amino}-indan-5-yl)-4-methanesulfonyl-benzamide7, MS: 388([M+H]⁺);

4-(4-{propyl-[6-(thiazole-2-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-butyl)-[1,4]diazepan-5-one8, MS: 505([M+H]⁺);

4-{4-[ethyl-(5-methoxy-indan-2-yl)-amino]-butyl}-[1,4]diazepan-5-one 9,MS: 360([M+H]⁺);

4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one10, MS: 418([M+H]⁺);

4-[4-(ethyl-indan-2-yl-amino)-butyl]-[1,4]diazepan-5-one 11; MS:330([M+H]⁺).

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one13, MS: 374([M+H]⁺);

4-{4-[ethyl-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-butyl}-[1,4]diazepan-5-one16, MS: 374([M+H]⁺);

4-{4-[(7-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one22, MS: 416([M+H]⁺);

methanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 38, MS: 452([M+H]⁺);

ethanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 39, MS: 466([M+H]⁺);

propane-1-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 40, MS: 480([M+H]⁺);

propane-2-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 41, MS: 480([M+H]⁺);

trifluoro-methanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 42, MS: 506([M+H]⁺);

benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 43, MS: 514([M+H]⁺);

thiophene-2-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 44, MS: 520([M+H]⁺);

phenyl-methanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 45, MS: 528([M+H]⁺);

3,5-dimethyl-isoxazole-4-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 46, MS: 533([M+H]⁺);

4-methoxy-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 47, MS: 544([M+H]⁺);

4-chloro-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 48, MS: 548([M+H]⁺);

4-chloro-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 49 MS: 548([M+H]⁺);

3-chloro-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 50, MS: 548([M+H]⁺);

dimethyl-sulfamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 51, MS: 481 ([M+H]⁺);

pyrrolidine-1-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 52, MS: 507([M+H]⁺);

4-{4-[(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one61, MS: 494([M+H]⁺);

4-{4-[(7-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one65, MS: 374([M+H]⁺);

1-Methyl-1H-imidazole-4-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 66, MS: 518([M+H]⁺);

4-{4-[(7-Phenoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one67, MS: 450([M+H]⁺);

trifluoro-acetic acid;4-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one71, MS: 403([M+H]⁺);

4-{5-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one73, MS: 417([M+H]⁺);

4-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one75, MS: 402([M+H]⁺);

N-(7-{[4-(7-Oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-propionamide76, MS: 429([M+H]⁺);

cyclopropanecarboxylic acid(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide77, MS: 441 ([M+H]⁺);

N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-isobutyramide78, MS: 443([M+H]⁺);

2,2-dimethyl-N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-propionamide79, MS: 457([M+H]⁺);

3,3-dimethyl-N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-butyramide80, MS: 457([M+H]⁺);

pyrrolidine-1-sulfonic acid(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide81, MS: 506 ([M+H]⁺);

4-(4-{[7-(2,2-dimethyl-propylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-amino}-butyl)-[1,4]diazepan-5-one82, MS: 443 ([M+H]⁺);

4-{4-[(7-cyclohexylamino-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one83, MS: 455 ([M+H]⁺);

1-isopropyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-urea84, MS: 458 ([M+H]⁺);

1-ter-butyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-urea85, MS: 472 ([M+H]⁺);

1-benzoyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-urea86, MS: 520 ([M+H]⁺);

4-{4-[(S)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one87, MS: 388 ([M+H]⁺);

4-{5-[(R)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one88, MS: 402 ([M+H]⁺);

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one90, MS: 388 ([M+H]⁺);

ethanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 94, MS: 466 ([M+H]⁺);

propane-2-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 95, MS: 466 ([M+H]⁺);

benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 96, MS: 514 ([M+H]⁺);

phenyl-methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 97, MS: 528 ([M+H]⁺);

4-methoxy-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 98, MS: 544 ([M+H]⁺);

2-chloro-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 99, MS: 548 ([M+H]⁺);

pyrrolidine-1-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 100, MS: 507 ([M+H]⁺);

methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 101, MS: 452 ([M+H]⁺);

propane-1-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 102, MS: 480 ([M+H]⁺);

trifluoro-methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 103, MS: 506 ([M+H]⁺);

1-methyl-1H-imidazole-4-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 104, MS: 518 ([M+H]⁺);

thiophene-2-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yleste105, MS: 520 ([M+H]⁺);

3,5-dimethyl-isoxazole-4-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 106, MS: 533 ([M+H]⁺);

4-chloro-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 107, MS: 548 ([M+H]⁺);

3-chloro-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 108, MS: 548 ([M+H]⁺);

dimethyl-sulfamic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 109, MS: 548 ([M+H]⁺);

4-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino)-butyl}-[1,4]diazepan-5-one110, MS: 402 ([M+H]⁺);

4-{4-[(6-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-(1,4]diazepan-5-one113, MS: 416 ([M+H]⁺); trifluoro-methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 140, MS: 508 ([M+H]⁺);

4-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one141, MS: 436 ([M+H]⁺);

4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one142, MS: 402 ([M+H]⁺);

4-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one150, MS: 402 ([M+H]⁺);

4-{5-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one152, MS: 416 ([M+H]⁺);

4-{3-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-propyl}-[1,4]diazepan-5-one153, MS: 388 ([M+H]⁺);

4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one157, MS: 436 ([M+H]⁺);

dimethyl-carbamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 167, MS: 445 ([M+H]⁺);

morpholine-4-carboxylic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 168, MS: 487 ([M+H]⁺);

isopropyl-carbamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 169, MS: 459 ([M+H]⁺);

propyl-carbamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 170, MS: 459 ([M+H]⁺); or

4-{5-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one172, MS: 432 ([M+H]⁺).

Example 6 Alternative Preparation of a Compound of Formula ID asDescribed in Scheme D1-(2-Dimethylamino-ethanesulfonyl)-4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one(24)

To a solution of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-onedihydrochloride (732 mg, 1.6 mmol), prepared as in Example 1, andtriethylamine (0.78 mL, 5.6 mmol) in methylene chloride (20 mL) underinert atmosphere was added 2-chloroethane sulfonyl chloride (0.17 mL,1.6 mmol). The reaction mixture was allowed to stir at room temperaturefor 4 hours, and was quenched with 2% sodium carbonate. The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo to affordthe chloroethylsulfonamide as a yellow oil.

To the chloroethylsulfonamide (1.6 mmol) and triethylamine (0.5 mL, 3.6mmol, 2.25 eq.) in methylene chloride (30 mL) under inert atmosphere wasadded dimethylamine hydrochloride (148 mg, 1.8 mmol). The reaction wasallowed to stir at room temperature for 20 hours, then concentrated invacuo. The remaining oil was chromatographed over silica gel to affordthe free base as a clear oil. The free base (215 mg, 0.41 mmol) wastaken up in diethyl ether and treated with 1M HCl in ether (0.82 mL).The solid was collected and dried under vacuum to afford4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one24 as a dihydrochloride (238 mg). (M+H)⁺=523

Similarly, following the procedures described above in Example 6, butoptionally replacing4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-onedihydrochloride with other free amine compounds of Formula ID, andoptionally replacing chloroethylsulfonamide with other appropriateacylating, alkylating, or sulfonylating agents, and utilizingmodifications known to those skilled in the art, the additionalcompounds of Formula I wherein Z is NR⁴ were prepared:

1-(2-dimethylamino-ethanesulfonylmethyl)-4-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one6, MS: 523 ([M+H]⁺).

Example 7 Alternative Preparation of a Compound of Formula ID asDescribed in Scheme D4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one(18)

To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca.13 mg50 μmole) prepared as described in Example 1, was added 440 μL solutionof 4-(6-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.125 M in 1,2dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 Mslurry of sodium triacetoxyborohydride in 1,2 dichloroethane. Thereaction was shaken at room temperature for 48 h. After quenching with 2mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL waterand ethyl acetate to workup flasks. The organic phase was washed, driedand concentrated. Purification by chromatography yielded3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one18, MS: 375 ([M+H]⁺).

Similarly, following the procedure described above in Example 7, butoptionally replacing 4-(6-oxo-[1,4]oxazepan-4-yl)-butyraldehyde withother appropriate compounds of formula 1e and optionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinZ is O were prepared:

4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one26, MS: 419([M+H]⁺);⁴-{4-[(7-Isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one34, MS: 417 ([M+H]⁺);

4-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one56, MS: 395 ([M+H]⁺);

4-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one68, MS: 404 ([M+H]⁺);

4-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one116, MS: 403 ([M+H]⁺);

4-{4-[(6-Ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one143, MS: 403 ([M+H]⁺); or4-{4-[(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one160, MS: 439 ([M+H]⁺).

Example 8

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate  0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Example 9

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0%  Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5%  PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Example 10

Composition for Oral Administration Ingredient Amount Active compound1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 gPropyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5mg Distilled water q.s. to 100 mL

The ingredients are mixed to form a suspension for oral administration.

Example 11

Parenteral Formulation (IV) Ingredient % wt./wt. Active ingredient 0.25g Sodium Chloride qs to make isotonic Water for injection to 100 mL

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Example 12

Suppository Formulation Ingredient % wt./wt. Active ingredient  1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Example 13

Topical Formulation Ingredients grams Active compound 0.2-2 Span 60 2Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Example 14 Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 15 Radioligand Binding Studies

The inhibitory activity of compounds of this invention in vitro wasdetermined using a modification of the method described in Hegde, S. S.et al. (1997) Br. J. Pharmacol., 120, 1409-1418.

Cell membranes from Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (m₁-m₅) were employed. The assayswere conducted with the radioligand [³H]N-methyl scopolamine(0.4 nM,specific activity 84 Ci-mmol⁻¹) in a final volume of 0.25 mL Tris-Krebsbuffer. Non-specific binding was defined with 1 μM atropine. Assays wereperformed using scintillation proximity assay technology.Competition-displacement curves were generated using 10 concentrationsof test compounds and were analyzed by iterative curve fitting to a fourparameter logistic equation. pIC₅₀ values (-log of the IC₅₀) wereconverted to pKi values using the Cheng-Prusoff equation.

Compounds of this invention were active in this assay.

Example 16 Oxotremorine/Pilocarpine-Induced Salivation (OIS/PIS) Modelin Anesthetized Rats.

Female Sprague-Dawley rats (Charles-River, 200-300 g) rats wereanesthetized with urethane (1.5 g/kg, sc) and were tracheotomized. Onefemoral vein was cannulated for drug administration. After a one hourstabilization period, rats were pre-treated with methoctramine (only forOIS) to antagonize M₂ receptor mediated bradycardia. Each animal wasdosed, intravenously, with a single dose of the vehicle or the referencecompound. Ten minutes later, pre-weighed cotton pads were placed in theanimals mouth following which they were dosed with vehicle oroxotremorine (0.1 mg/kg, iv)/pilocarpine (1 mg/kg, iv). Fresh cottonpads were placed at 5 minutes post-oxotremorine/pilocarpine and salivacollected for an additional 5 minutes. The cotton pads (5 and 10-minuteperiod) were then re-weighed to determine the amount of saliva secretedduring the 10-minute period.

All oxotremorine/pilocarpine treated groups were compared using one-wayanalysis of variance. Pair-wise comparisons were made using Dunnett'stest. The ranked data (non-parametric technique) or actual levels of thedata (parametric technique) are applied in the analysis depending uponthe results of the Bartlett's test, which tests homogeneity ofvariances. The vehicle/oxotremorine group and vehicle/pilocarpine wascompared to the vehicle/vehicle group using Wilcox on rank-sum test. Anestimate of the ID₅₀ for each compound with respect to the 10 minuteoverall secretion weight for each animal was obtained. The sigmoidalmodel is in the form of

Resp=min+(max−min)/(1+(dose/ID ₅₀)**N)

where ID₅₀ is the dose to achieve half the maximal response, N is thecurvature parameter and max is the max response for the dose responsecurve. The minimum response was fixed at 0 in the model.

Compounds of this invention were active in this assay.

Example 17 Inhibition of Volume-Induced Contractions in Rats

The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in rats using a modification of themethod described in Hegde, S. S. et al.(1996) Proceedings of the 26thAnnual Meeting of the International Continence Society (August27th-30th), Abstract 126.

Female Sprague-Dawley rats were anesthetized with urethane andinstrumented for intravenous administration of drugs and, in some cases,measurement of arterial pressure, heart rate and intra-bladder pressure.The effect of test compounds on volume-induced bladder contractions wasdetermined in separate groups of animals. Volume-induced reflex bladdercontractions were induced by filling the bladder with saline. The testcompounds were administered intravenously in a cumulative manner at10-minute intervals. Atropine (0.3 mg/kg, iv) was administered at theend of the study as a positive control.

Compounds of this invention were active in this assay.

Example 18 Anti-Muscarinic Activity in Anesthetized Dogs

The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in dogs using a modification of themethod described in Newgreen, D. T. et al.,(1996) J. Urol., 155 (Suppl.5), 1156.

Female beagles (Marshall Farms, North Rose, N.Y.) were fasted for 18hours prior to the experiment; water was allowed ad libitum. On the dayof the experiment, dogs were anesthetized and maintained onpentobarbital (36 mg/kg, iv initially, then 5-10 mg/kg, iv formaintenance). Intravenous fluids were also administered to the dog forthe remainder of the experiment. The dogs were artificially ventilated,via an endotracheal tube, with an Harvard respirator (Model 613). Bothfemoral veins and one femoral artery was cannulated for drugadministration and blood pressure measurement, respectively. Bloodpressure was measured with a Gould transducer (Model P23XL) and recordedon a Gould recorder (Model 3400). A sublingual incision was made toexpose the left mandibular duct, which was then cannulated for thecollection of saliva into pre-weighed vials. The left salivary gland wasexposed via a submandibular incision. The chorda-lingual nerve wasisolated and had a bipolar electrode placed on it for stimulation. Testresponses to chorda-lingual nerve stimulation were obtained to confirmproper electrode placement.

After completion of surgery, physostigmine (180 μg/kg/hr, iv) (acholinesterase inhibitor) was infused for the remainder of theexperiment. Following a one hour stabilization period, two controlchorda-lingual nerve stimulations were performed at 12 Hz, 10 V, 0.5 msduration (Grass S48). The chorda-lingual nerve was stimulated for 20seconds and 2 minutes, respectively, with a minimum of 10 minuteinterval between each set of stimulations. After two consistent controlresponses were obtained, the vehicle or the reference compound was dosedin a cumulative fashion, 3 minutes prior to each stimulation of thechorda-lingual nerve. Experiments in which consistent salivationresponses could not be obtained were not included in the analysis.Atropine (1.0 mg/kg, iv) was given as a positive control at the end ofthe study.

Mean arterial blood pressure was calculated as Diastolic arterialpressure+(Systolic arterial pressure−Diastolic arterial pressure)/3.Heart rate was derived from the pressure pulse. Saliva was collected inpre-weighed vials and weighed after each collection to determine thevolume of saliva secreted. Inhibition of salivary gland responses wereexpressed as a percent of the effect of atropine (1 mg/kg, iv).

ED50 Estimation

For % max inhibition salivation, parameter estimation was performedusing a nonlinear mixed model. The method was implemented using PROCNLIN initially and PROC MIXED iteratively. This procedure assumed thefollowing sigmoidal dose-response model:${Response} = {{Min} + \frac{{Max} - {Min}}{1 + 10^{- \frac{({x - \mu})}{\sigma}}}}$

where response=% max inhibition bladder contraction at peak, x=log₁₀dose of treatment and the 4 parameters were: log₁₀ ED50 (μ), maximum andminimum response (Max and Min), and curvature (σ). The minimum wasassumed 0%. This method assumed compound symmetry for the covariancestructure. It was an iterative curve-fitting procedure that accountedfor the dependence between multiple measurements from the same animal,and estimated the desired parameters and their confidence limits byadjusting its error calculations to account for within subjectcorrelation.

Baseline Comparisons

To compare each dose to baseline control for every variable, a two-wayANOVA with main effects of subject and treatment was performed, followedby a pair t-test at each dose level. If the overall treatment effect wasnot significant (p-value>0.05) in ANOVA, a Bonferroni adjustment forp-values was used for the p-value of pair t-test at each dose.

Compounds of this invention were active in this assay.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of Formula I

wherein: R¹, and R² are independently in each occurrence hydrogen,halogen, (C₁₋₆)-alkyl, —OR′, —SR′, —NR′R″, —SOR′, —SO₂R′, —COOR′,—OCOR′, —OCONR′R″, —OSO₂R′, —OSO₂NR′R″; —NR′SO₂R″, —NR′COR″, —SO₂NR′R″,—SO₂(CH₂)₁₋₃CONR′R″, —CONR′R″, cyano, haloalkyl, or nitro; R′ and R″ areindependently in each occurrence hydrogen, (C₁₋₆)-alkyl, substitutedlower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C₁₋₃)-alkyl,heteroaryl-(C₁₋₃)-alkyl, heterocyclyl-(C₁₋₃)-alkyl, cycloalkylalkyl,cycloalkyl, or R′ and R″ together with the nitrogen they are attachedmay also form a 5- to 7-membered ring, optionally incorporating oneadditional ring heteroatom chosen from N, O or S(O)₀₋₂; R³ isindependently in each occurrence (C₁₋₆) alkyl, (C₁₋₆) alkenyl, (C₁₋₆)alkynyl, or cycloalkyl; R⁴ is hydrogen, (C₁₋₆)-alkyl, haloalkyl,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, —(C₁₋₆)—CR′R′R′, —COOR′, —SO₂R′,—C(O)R′, —SO₂(CH₂)₀₋₃NR′R″, —CONR′R″, or —PO(OR′)₂, wherein R′ and R″are as defined above; “substituted lower alkyl” means the lower alkylhaving one to three substituents, selected from the group consisting ofhydroxyl, alkoxy, amino, amido, carboxyl, ncyl, halogen, cyano, nitroand thiol; “heteroaryl” means the monovalent aromatic cyclic radicalhaving one to three rings of four to eight atoms per ring, incorporatingone or two heteroatoms (chosen from nitrogen, oxygen or sulfur), withinthe ring which can optionally be substituted with one or twosubstituents selected from the group consisting of hydroxy, cyano, loweralkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,alkylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino;“heterocyclyl” means the monovalent saturated cyclic radical, consistingof one or two rings, of three to eight atoms per ring, incorporating oneor more ring heteroatoms (chosen from N,O or S(O)₀₋₂), and which canoptionally be substituted with one or two substituents selected from thegroup consisting of hydroxy, oxo, cyano, lower alkyl, lower alkoxy,lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro,alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl,alkylaminosulfonyl arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino and arylcarbonylamino; “cycloalkyl” means themonovalent saturated carbocyclic radical consisting or one or two rings,of three to eight carbons per ring, which can optionally be substitutedwith one or two substitutents, selected from the group consisting ofhydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio,halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino; p is aninteger from 1 to 3 inclusive; n is an integer from 1 to 6 inclusive;and, individual isomers, racemic or non-racemic mixtures of isomers, orpharmaceutically acceptable salts or solvates thereof.
 2. The compoundof claim 1, wherein p is
 2. 3. The compound of claim 1, wherein n is 3.4. The compound of claim 2, wherein n is
 3. 5. The compound of claim 4,wherein R⁴ is hydrogen.
 6. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 in admixturewith a pharmaceutically acceptable carrier.
 7. A method of treating asmooth muscle disorder of the genitourinary tract selected from thegroup consisting of overactive bladder, detrusor hyperactivity, urgency,frequency, reduced bladder capacity, incontinence episodes, changes inbladder capacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, outlet obstruction, outlet insufficiency, pelvichypersensitivity, idiopathic conditions and detrusor instabilitycomprising administering a therapeutically effective amount of acompound according to claim
 1. 8. A method of treating a respiratorysmooth muscle disorder selected from the group consisting of allergies,asthma, chronic obstructive pulmonary disease and pulmonary fibrosiscomprising administering a therapeutically effective amount of acompound according to claim
 1. 9. A method of treating agastrointestinal smooth muscle disorder selected from the groupconsisting of irritable bowel syndrome, diverticular disease,gastrointestinal hypermobility disorders and diarrhea comprisingadministering a therapeutically effective amount of a compound accordingto claim
 1. 10. A process for preparing a compound as claimed in claim 1which process comprises reacting a compound having a formula

with a compound of formula

to provide a compound of Formula I

wherein R¹, R², R³, R⁴ p and n are as defined in claim 1.